Advances in Metallodrugs

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Advances in Metallodrugs

Preparation and Applications in Medicinal Chemistry

Edited byShahid-ul-Islam, Athar Adil Hashmi

and Salman Ahmad Khan

This edition first published 2020 by John Wiley & Sons, Inc., 111 River Street, Hoboken, NJ 07030, USA and Scrivener Publishing LLC, 100 Cummings Center, Suite 541J, Beverly, MA 01915, USA© 2020 Scrivener Publishing LLCFor more information about Scrivener publications please visit www.scrivenerpublishing.com.

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Library of Congress Cataloging-in-Publication Data

ISBN 978-1-119-64042-4

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Set in size of 11pt and Minion Pro by Manila Typesetting Company, Makati, Philippines

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10 9 8 7 6 5 4 3 2 1

v

Contents

Preface xiii1 Metallodrugs in Medicine: Present, Past, and Future Prospects 1

Imtiyaz Yousuf and Masrat Bashir 1.1 Introduction 21.2 Therapeutic Metallodrugs 6

1.2.1 Anticancer Metallodrugs 61.2.1.1 Mechanism of Anticancer Action 7

1.2.2 Antimicrobial and Antiviral Metallodrugs 151.2.2.1 Antimicrobial Metallodrugs 151.2.2.2 Antiviral Metallodrugs 16

1.2.3 Radiopharmaceuticals and Radiodiagnostic Metallodrugs 171.2.4 Anti-Diabetic Metallodrugs 191.2.5 Catalytic Metallodrugs 22

1.3 Future Prospects 231.4 Conclusion 25 References 26

2 Chemotherapeutic Potential of Ruthenium Metal Complexes Incorporating Schiff Bases 41Manzoor Ahmad Malik, Parveez Gull, Ovas Ahmad Dar, Mohmmad Younus Wani, Md Ikbal Ahmed Talukdar and Athar Adil Hashmi2.1 Introduction 422.2 Schiff Base Complexes of Ruthenium as Anticancer Agents 432.3 Conclusion 63 References 64

3 Role of Metallodrugs in Medicinal Inorganic Chemistry 71Manish Kumar, Gyanendra Kumar, Arun Kant and Dhanraj T. Masram3.1 Introduction 72

vi Contents

3.2 Platinum Anticancer Drugs 743.2.1 Nucleophilic Displacement Reactions in Complexes

of Platinum 803.2.2 Mode of the Interaction of Cisplatin Species

With Nitrogen Donors of DNA Strand 803.2.3 Systemic Toxicity of Cisplatin 82

3.3 Copper-Based Anticancer Complexes 823.3.1 Copper is Essential for Health and Nutrition 823.3.2 Healthcare Applications of Copper 833.3.3 Copper and Human Health Disorders 83

3.3.3.1 Wilson’s Disease (WD) 843.3.3.2 Menkes’ Disease 85

3.3.4 Role of Copper Complexes as Potential Therapeutic Agents 853.3.4.1 Thiosemicarbazones-Based Complexes 863.3.4.2 Quinolones-Based Copper Complexes 883.3.4.3 Naphthoquinones 88

3.4 Zinc Anticancer Complexes 893.4.1 Biologically Importance of Zinc 903.4.2 Schiff Base Chemistry 92

3.4.2.1 Schiff Base and Their Metal Complexes 923.4.3 Zinc-Based Complexes 933.4.4 Top Food Sources of Zinc 943.4.5 Role of Zinc in Human Body 973.4.6 Zinc as a Health Benefit 983.4.7 Zinc in Alloy and Composites 1003.4.8 Zinc Supplementation as a Treatment 100

3.4.8.1 Zinc Deficiency 1013.4.8.2 Zinc Toxicity 1023.4.8.3 Zinc and Viral Infections 102

3.4.9 Gastrointestinal Effects 1033.5 Future Prospects of Metallodrugs 103 References 104

4 Ferrocene-Based Metallodrugs 115Hamza Shoukat, Ataf Ali Altaf and Amin Badshah4.1 Introduction 1154.2 Ferrocene-Based Antimalarial Agents 117

4.2.1 Mechanism of Action 1184.3 Ferrocene-Based Antibacterial and Antifungal Drugs 118

4.3.1 Schiff Base Derived Ferrocene Conjugates as Antibacterial Agents 119

Contents vii

4.3.2 Ferrocenyl Guanidines as Antibacterial and Antifungal Agents 121

4.3.3 Sedaxicene as Antifungal Agents 1224.4 Ferrocene-Based Anti-Tumor and Anti-Cancerous Drugs 123

4.4.1 Ferricenium Salts as Anti-Tumor Agents 1244.4.2 Ferrocenylalkylazoles Active Anti-Tumor Drugs 1244.4.3 Ferrocene Conjugated to Peptides for Lung Cancer 1254.4.4 Ferrocenylalkyl Nucleobases Potential

Anti-Cancerous Drugs 1264.4.5 Ferrocenyl Sub-Ordinates of Illudin-M 1264.4.6 Ferrocenyl Derivatives of Retinoids Potential

Anti-Tumor Drug 1274.4.7 Targeting Breast Cancer With Selective

Ferrocene-Based Estrogen Receptor Modulators (SERM) 128

4.5 Conclusion 1314.6 Future of Ferrocene-Based Drugs 131 References 132

5 Recent Advances in Cobalt Derived Complexes as Potential Therapeutic Agents 137Manzoor Ahmad Malik, Ovas Ahmad Dar and Athar Adil Hashmi5.1 Introduction 1375.2 Cobalt Complexes as Potential Therapeutic Agents 1385.3 Conclusion 153 References 154

6 NO-, CO-, and H2S-Based Metallopharmaceuticals 157R. C. Maurya and J. M. Mir 6.1 Introduction 1586.2 Signaling Molecules: Concept of “Gasotransmitter” 160

6.2.1 Therapeutic Applications of NO, CO, and H2S 1626.2.1.1 Exogenous NO Donating Molecules 163

6.3 NO Donors Incorporated in Polymeric Matrices 1676.3.1 Metal Nitrosyl Complexes 168

6.3.1.1 Sodium Nitroprusside (SNP) 1686.4 Dinitrosyl Iron Thiol Complexes (DNICs) 1706.5 Photoactive Transition Metal Nitrosyls as NO Donors 1706.6 Exogenous CO Donating Molecules 1736.7 H2S Donating Compounds 176

6.7.1 H2S Gas: A Fast Delivering Compound 176

viii Contents

6.7.2 Sulfide Salts: Fast Delivering H2S Compounds 1776.7.3 Synthetic Moieties 178

6.7.3.1 Slow-Delivering H2S Compounds 1786.7.3.2 H2S-Releasing Composite Compounds 179

6.7.4 Naturally Occurring Plant Derived Compounds 1826.7.4.1 Garlic 1826.7.4.2 Broccoli and Other Cruciferous Vegetables 184

6.8 Concluding Remarks and Future Outlook 185 References 186

7 Platinum Complexes in Medicine and in the Treatment of Cancer 203Rakesh Kumar Ameta and Parth Malik7.1 What is Cancer? 203

7.1.1 Characteristic Features of Cancer Cells 2057.1.2 Definition of Anticancer Compound 2067.1.3 Anticancer Attributes of Pt Complexes 2077.1.4 Native State Behavior of Pt Complexes 208

7.2 Compatibility of Pt Compounds in Cancer Treatment 2097.2.1 Significance of DNA as Primary Target 2097.2.2 Kinetics of DNA Binding Activities 2107.2.3 Structural and Regioselectivity of DNA Adducts 2107.2.4 Studies on Action Mechanism 211

7.3 Pt Complexes as Anticancer Drugs 2147.3.1 DNA-Coordinating Pt(II) Complexes 2147.3.2 DNA-Covalently Binding Pt(II) Complexes 2197.3.3 Targeted Pt(II) Complexes 2227.3.4 Pt(IV) Prodrugs 2247.3.5 Multiple Action of Pt(IV) Prodrugs 2257.3.6 Targeted Pt(IV) Prodrugs 2287.3.7 Photodynamic Killing of Cancer Cell

by Pt Complexes 2317.4 Conclusion 231 Acknowledgments 232 References 232

8 Recent Advances in Gold Complexes as Anticancer Agents 247Mohammad Nadeem Lone, Zubaid-ul-khazir, Ghulam Nabi Yatoo, Javid A. Banday and Irshad A. Wani8.1 Introduction 2488.2 Evolution of Metal Complexes as Anticancer Agents 250

Contents ix

8.3 Gold Complexes 2518.3.1 Complexes with Nitrogen Donar Ligands 2528.3.2 Complexes with Sulphur Donar Ligands 2548.3.3 Complexes with Phosphorus Donar Ligands 2558.3.4 Complexes with Sulphur-Phosphorus Donar Ligands 2568.3.5 Organometallic Gold Complexes 2598.3.6 Miscellaneous 260

8.4 Nano-Formulations of Gold Complexes 2628.5 Future Challenges and Perspectives 2638.6 Conclusion 265 Acknowledgements 266 References 266

9 Recent Developments in Small Molecular HIV-1 and Hepatitis B Virus RNase H Inhibitors 273Fenju Wei, Dongwei Kang, Luis Menéndez-Arias, Xinyong Liu and Peng Zhan9.1 Introduction 273

9.1.1 Activity and Function of HIV and HBV RNases H 2749.1.2 The Metal-Chelating RNase H Active Site 274

9.2 RNase H Inhibitors and Strategies in the Discovery of Active Compounds 2769.2.1 High-Throughput Screening 2769.2.2 Design Based on Pharmacophore Models 2789.2.3 Novel Inhibitors Obtained by Using

“Click Chemistry” 2799.2.4 Dual-Target Inhibitors Against HIV-1 Integrase (IN)

and RNase H 2809.2.5 Inhibitors Obtained by Using Privileged

Fragment-Based Libraries 2829.2.6 RNase H Inhibitors in Natural Products 2839.2.7 Drug Repurposing Based on Privileged Structures 284

9.3 Conclusion 286 References 287

10 The Role of Metals and Metallodrugs in the Modulation of Angiogenesis 293Mehmet Varol and Tuğba Ören Varol10.1 Introduction 29410.2 Metallodrugs in Anticancer Therapy 29710.3 Angiogenesis as a Substantial Target

of Tumorigenesis 300

x Contents

10.4 Metals and Metallodrugs in Angiogenesis 30210.5 Concluding Remarks and Future Prospects 306 References 306

11 Metal-Based Cellulose: An Attractive Approach Towards Biomedicine Applications 319Kulsoom Koser and Athar Adil Hashmi11.1 Introduction 32011.2 History of Cellulose 32011.3 The Properties and Structure of Cellulose 32111.4 Modification of Cellulose 322

11.4.1 Acid Hydrolysis 32211.4.2 Oxidation 32411.4.3 Esterification 32611.4.4 Amidation 33111.4.5 Carbamiation 33311.4.6 Etherification 33611.4.7 Nucleophilic Substitution 33911.4.8 Further Modification 341

11.5 Present and Future Medical Applications of Cellulose as Well as Its Components 34411.5.1 Cellulose Used as Wound Dressing 34411.5.2 Dental Applications 34511.5.3 Engineering 34611.5.4 Controllable Drug Delivery System 34811.5.5 Blood Purification 34811.5.6 Wrapping Purpose 35011.5.7 Renal Failure 351

11.6 Conclusion 351 References 352

12 Multifunctional Nanomedicine 363Nobel Tomar, Maroof A. Hashmi and Athar Adil Hashmi12.1 Introduction 36412.2 Diagnostics and Imaging 36612.3 Drug Delivery and Therapy 369

12.3.1 Drug Delivery by Organic Nanomaterials 36912.3.1.1 Liposomal Drug Delivery 36912.3.1.2 Polymeric Drug Delivery 37112.3.1.3 Proteins and Peptides for

Drug Delivery 373

Contents xi

12.3.2 Drug Delivery by Inorganic Nanomaterials 37412.3.2.1 Metal and Metal Oxides 37412.3.2.2 Au NPs 37512.3.2.3 Carbon-Based NPs 37512.3.2.4 Silicon-Based Nanostructures

for Drug Delivery 37812.3.3 Photo Therapy 379

12.3.3.1 Photodynamic Therapy 38012.3.3.2 Photothermal Therapy 381

12.3.4 Radiation Therapy 38312.3.5 Neutron Capture Therapy 384

12.4 Regenerative Medicine 38512.5 Future Prospects and Conclusion 386 References 387

Index 403

xiii

Preface

Over the past few decades, medicinal inorganic chemistry as an interdisci-plinary sub-area of bioinorganic chemistry has received the growing atten-tion of researchers in the search for promising antimicrobial, antimalarial, antiviral, and antitumor chemotherapeutic agents. An excellent compila-tion of reports on metal complexes has revealed the potency of metal com-plexes as better therapeutic agents. Metal-containing drugs have several promising advantages over organic ligands and have gained the trust of researches after the worldwide approval of the drug cisplatin. Their dis-tinct mechanism of action makes them perfect candidates as alternatives to the conventional drugs to which resistance has already been shown. In this direction, a huge number of transition metal complexes have been synthesized and evaluated for their biological profiles.

This book is organized into 12 important chapters that focus on the progress made by metal-based drugs as anticancer, antibacterial, anti-viral,  anti-inflammatory, and anti-neurodegenerative agents, as well as highlights the application areas of newly discovered metallodrugs. It can prove beneficial for researchers, investigators, and scientists whose work involves inorganic and coordination chemistry, medical science, phar-macy, biotechnology, and biomedical engineering.

We are indebted to all the authors for their commitment and for bring-ing their knowledge and professional experience to making this project a reality. Last but not least, the editors would like to thank Mr. Martin Scrivener, President of Scrivener Publishing, USA, who accepted and sup-ported this project.

Shahid-ul-Islam Athar Adil Hashmi

Salman Ahmad KhanApril 2020

1

Shahid-ul-Islam, Athar Adil Hashmi and Salman Ahmad Khan (eds.) Advances in Metallodrugs: Preparation and Applications in Medicinal Chemistry, (1–40) © 2020 Scrivener Publishing LLC

1

Metallodrugs in Medicine: Present, Past, and Future Prospects

Imtiyaz Yousuf* and Masrat Bashir

Department of Chemistry, Aligarh Muslim University, Aligarh, India

AbstractMetal coordination complexes on account of their unique properties of metals which includes variable oxidation states, geometry, coordination numbers, redox behavior, and ability to bind to a wide variety of types of ligands offer a versatile platform for the design of novel therapeutic and diagnostic agents. The therapeu-tic potential of metal ions can be optimized by tethering it to a suitable frame work that not only tune but synchronize the organic ligand scaffold to act in concord at the target site. Medicinal inorganic chemistry is a growing interdisciplinary field of pharmaceutical research which involves design of therapeutic and diagnostic agents with emphasis on medicinal use for the treatment of various chronic dis-eases. The serendipitous discovery of cisplatin, inorganic anticancer drug opened up new prospects in the area of medicinal inorganic chemistry that not only cured cancer but provided a continuous spur towards the development of new metal-lodrugs that can address the serious challenges in the drug regime. Thus, many metal-based therapeutics and diagnostic agents have been explored extensively for their diverse applications as artificial metalloenzymes, DNA foot-printing agents, and nucleic acid structural probes, etc. Given the premises of metallodrugs in the medicinal field, this chapter focuses on the progress made by metal-based drugs as anticancer, anti-bacterial, anti-viral, anti-inflammatory, and anti- neurodegenerative agents, as well as emphasis on the new strategies to be used in the development of new potential metallodrugs.

Keywords: Medicinal inorganic chemistry, metallodrugs, metal-coordination complexes, therapeutic and diagnostic agents, chronic diseases, drug delivery, prodrugs

*Corresponding author: imtiyazchem@gmail.com

2 Advances in Metallodrugs

1.1 Introduction

Medicinal inorganic chemistry is an interdisciplinary sub-area of bioinor-ganic chemistry field which tethers the applications of inorganic chemis-try and biological disciplines, thereby investigate the intriguing properties of metal ions, their complexes, and other metal binding compounds for the therapeutic and diagnostic purposes [1–6]. Conceptually, the field of medicinal inorganic chemistry includes the biomimetic chemistry of metal ions in metalloproteins [7, 8], identification of metal ions in pathogenic protein misfolding [9, 10], functions of endogenous and exogenous metal ions at the molecular level [11, 12], and the homeostasis of metal ions in living systems [13]. The use of several metals (Cu, Au, Ag, Hg, and As) can be traced back to ancient civilizations (Mesopotamia, Egypt, India, and China) [14] with the recognition by the Egyptians who used copper to sterilize water with an understanding of disinfection and the Chinese and Arabs utilized gold in the treatment of many chronic diseases [15]. Zinc was found to promote healing of wounds while mercurous chloride was used as a diuretic. Paul Ehrlich the “founder of chemotherapy” devel-oped arsenical, Salvarsan, as a drug for the treatment of Syphilis in early twentieth century (Figure 1.1) [16]. Thus, a link between the discovery of a new elements and their application into the medicinal armamentarium (therapeutic and diagnostic) has been exploited since antiquity (Table 1.1).

Numerous metal ions and their complexes have been routinely admin-istered to patients for therapeutic and diagnostic benefit such as platinum and ruthenium complexes in cancer therapy [17–20], gold complexes as anti-arthritis agents [21, 22], cobalt complexes as antiviral [23], and gado-linium and technetium as magnetic resonance imaging (MRI) contrasting agents [24–26] (Figure 1.2).

Metal ions can serve many important functions in the biological sys-tems; (i) functional role, i.e., the biological activity is due to direct binding

OH

OH

OH

OH

OH

HO

HO

H2N

H2N NH2

NH2

NH2

HO

H2N NH2

NH2

AsAs As

AsAsAs AsAs

(b)(a)

Figure 1.1 Structures of arsenic-based therapeutic drug, salvarsan (3‒amino‒4‒hydroxyphenyl‒arsenic(III) compounds).

Metallodrugs in Medicine 3

Table 1.1 The use of metal salts and their compounds as therapeutic and diagnostic agents.

Metal Metal-based salt/compound Therapeutic/diagnostic use

Ag Silver sulphadiazine Antibacterial

Al Al(OH)3 Antacid

As Salvarsan, Melarsen, Tryparsamide Antimicrobial

Au Gold(I) thiolatesAuranofin

AntitumourAntiarthritis

Ba Barium sulphate X‒ray contrast

Bi Bismuth subsalicylate, colloidal bismuth citrate, ranitidine bismuth citrate

Antacid, antiulcer

Cu Copper histidine complexCasiopeinas

Menkes disease Anticancer

Co Coenzyme B1Doxovir

SupplementAntiviral

Fe Sodium nitroprussideFe(III) desferrioxamine chelates

VasodilatorAntimicrobial

Gd Gd metallotexaphyrin (Magnevist, Dotarem)

MRI contrast agentRadiopharmaceuticals

Hg Mereurochrome Antiseptic

Li Li2CO3 Manic depression

Pt Cisplatin, carboplatin, oxaliplatin, nedapltin etc

Anticancer

Ru NAMI‒A, KP10109, RAPTA‒C etc Anticancer

Sb Pentostam, N‒methylglucamine antimonate

Antileishmanial

Tc 99mTc (V) propyleneamine oxime Diagnostic imaging

Ti Titanocene dichloride, bis(β‒diketonato) Ti(IV)

Anticancer

(Continued)

4 Advances in Metallodrugs

Table 1.1 The use of metal salts and their compounds as therapeutic and diagnostic agents. (Continued)

Metal Metal-based salt/compound Therapeutic/diagnostic use

V Bis(maltolato) oxovanodium(IV)Bis(glycinato) oxovanodium (IV)Bis(methylpicolinato oxovanadium

(IV)

Antidiabetic

W PolyoxometalJates Anti-HIV activity

Zn ZnOZn(II)bicyclam complexesZinc citrate/sulphate

Skin ointmentAntiviralSupplement

Zr Zr(lV) glycinato Antiperspirant

NH3Cl

Cl NH3

Pt

OS

AcO

AcOAcO

OAc

AuP

HO NH

HN

O

NH2

O

O

O

OH

S

As

Gd

N

N

O

O

O

ON

O OO

OO

OOH H

PO

O-O

(a)

(b)

(c) (d)

Figure 1.2 Prominent examples of metal-based drug in medicinal inorganic chemistry: (a) Cisplatin, (b) MS–325, (c) Darinaparsin, and (d) Auranofin.

Metallodrugs in Medicine 5

of the metal fragment to the target site [27], (ii) structural role, i.e., the shape of the complex is determined and binding to the biological target occurs through non-covalent interactions [28–30], (iii) act as a carrier for active ligands that are delivered in vivo [31, 32] and protect the ligand before its delivery at the target site, (iv) metal complexes behave as a cata-lyst in vivo by the production of reactive oxygen species (ROS) that cause cell damage [33, 34], and (v) metal complexes which are photoactive can act as photosensitizers [35, 36]. Metal ions once introduced into a bio sys-tem for therapeutic or diagnostic effect can also be removed from back by the judicious use of the chelating ligands (chelation therapy). Many pro-teins and enzymes bind one or more metal ions to perform their functions where the metal ion is involved in the catalytic mechanism or stabilizes the tertiary and quaternary structure of proteins.

Whereas the small organic drug molecules rely purely on carbon, their binding geometry in space is dictated by the hybridization, viz., sp (lin-ear), sp2 (trigonal-planar), and sp3 (tetrahedral) as compared to the diverse geometry in 3D space open to metal-based drugs [37]. Besides linear, square planar, and tetrahedral geometries, pyramidal, trigonal bipyrami-dal, and octahedral shapes can be created and even higher coordination numbers and geometries with larger metal ions are possible, all of these geometries exhibit a tremendous importance for biological phenomena that allow the fine-tuning of their chemical reactivity in terms of both kinetics (rates of ligand exchange) and thermodynamics (strengths of metal-ligand bonds, redox potentials, etc). Not only the metal but also the ligands can play important roles in biological activity, ranging from outer-sphere rec-ognition of the target site to the activity of any released ligands and ligand centered redox processes. Modification of substituents or ligands around the metal center, thus modulates drug entities to perform manifold func-tions and at specific target sites to combat chronic diseases, viz., cancers, HIV-AIDS, cardiovascular, cerebrovascular diseases, and respiratory dis-orders [38]. Since metal ion can participate in biological redox reactions, and many transition metals (Pt, Ru, Fe, Cu) possessing variable oxidation states offer many possibilities for strategic designs of new chemotherapeu-tics. Many literature reports reveal that the redox properties of the metal ions or the ligands can influence the mechanism of action of metal-based anticancer chemotherapeutic drugs [39–41]. Thus, in metal complexes, it is possible to trigger a desired biological response at the site of action and at the optimum time by controlling the activation process by substitution (ligand exchange) and/or redox processes.

6 Advances in Metallodrugs

One of the biggest challenges in enhancing the therapeutic potential of a metallodrug is its delivery to the selective targets. It is imperative for a prospective drug to demonstrate sufficient reactivity towards the selective biological target but less affinity towards other biomolecules encountered on the way which render its deactivation. Prodrugs are drug derivatives that can undergo in vivo transformation to release the active species, with improved physiochemical, biopharmaceutical, and pharmacokinetic prop-erties [42, 43]. The application of prodrug strategy encompasses the use of polymeric conjugate materials and other inclusions of metallodrug in liposomes, protein macromolecules, lipid-based systems, and dendrimers as drug carriers that limit its interaction with biomolecules other than the selected targets [44]. For metal-based therapeutics, this prodrug activation can be accomplished by in vivo ligand substitution, photochemical process and/or redox reactions before reaching the target site. It is thus important to ascertain the active part of the metal complex which is essential for ther-apeutic activity; the metal itself, the ligands and the intact delivery system. Thus, a rational state-of-art design of therapeutic and diagnostic agents is required to achieve specific targeting features and control toxicity (side effects) which can be achieved by controlling thermodynamic and kinetic processes of metal complexes.

1.2 Therapeutic Metallodrugs

1.2.1 Anticancer Metallodrugs

Cancer is a class of disease in which a group of cells display uncontrolled growth (division beyond the normal limits), invasion (intrusion and destruction of adjacent tissues), and sometimes metastasis (spread to other locations in the body via lymph or blood) [45]. Current statistics indicate that one in every three people will develop some form of cancer during their lifetime. It is estimated that by 2030, there will be 21.4 million new cases diagnosed every year [46]. Most cancerous cells divide uncontrolla-bly to form lumps or masses of tissue called tumors but some like leukemia (where cancer prohibits normal blood function by abnormal cell division in the blood stream) do not [47]. The complexity of the disease however, arises mainly due to the fact that cancers evolve from different tissues of origin, shows multiple etiologies or endless combinations of genetic or epigenetic alterations. The primary treatment modalities include surgery, chemotherapy, radiations, and immunotherapy, etc [48]. However, the mainstay treatment is based on chemotherapy which a viable alternative

Metallodrugs in Medicine 7

involving various natural and synthetic origin compounds that can kill or halt the unwanted proliferation of cancerous cells.

Metal-based antitumor chemotherapeutics gained prominence after the phenomenal serendipitous discovery of the archetypical inorganic drug, cisplatin (cis–diamminedichloroplatinum(II), [cis–(NH3)2PtCl2]) by B. Rosenberg in 1965 [49]. Cisplatin is one of the most effective chemo-therapeutic drug used for treating solid malignancies, viz., bladder, mel-anoma, non–small cell lung, small cell lung, head and neck, cervical, ovarian, and testicular cancers (>90% cure rate) [50]. Currently, it is used in 32 of 78 treatment regimens in combination with a wide range of other drugs including: topoisomerase II inhibitors (doxorubicin, etoposide, and bleomycin), mustards (cyclophosphamide, melphalan and ifosfamide), and antimetabolites [51].

1.2.1.1 Mechanism of Anticancer Action

Cisplatin initially enters inside the cell via both passive diffusion and active uptake where it undergoes a ligand substitution event prior to DNA bind-ing. Noticeably, inside the bloodstream (extracellular), cisplatin is relatively stable and maintains its neutral state, due to the high concentration of chlo-ride ions (∼100 mM). However, inside the cell (intracellular), the relatively low chloride ion concentration (∼4−12 mM) causes cisplatin to undergo aquation, in which a chloride ligand is replaced by a water molecule result-ing in the formation of cis‒[Pt(NH3)2Cl(H2O)]+ species having half-life of ca. 2 h for the aquation reaction. The positive charged platinum complex is a potent electrophile that is attract to the negatively charged nuclear DNA at the N7 position of purine bases of DNA with a release of the water mol-ecule [52]. The remaining cis-monochloride species ([Pt(NH3)2Cl(H2O)]+) is then subsequently aquated diaqaua species ([Pt(NH3)2(H2O)2]

+) allowing the cisplatin to cross-link to another purine. Moreover, the square-planar geometry of cisplatin facilitates ligand substitution, which is necessary for it to form the DNA lesions that characterize its activity. Cross-linking between adjacent guanine residues is considered to be crucial to the cytotoxicity of cisplatin. Such cross-links can occur between deoxyguanosines on the same strand or on different strands, giving rise to intrastrand and interstrand DNA cross-links, respectively. The 1,2‒d(GpG) intrastrand cross-link is the most prevalent lesion (65%), but 1,2‒(ApG) (25%) and 1,3‒d(GpTpG) (10%) intrastrand cross-links also form along with small amounts of GG interstrand crosslinks [53]. These adducts interfere with cellular DNA rep-lication and transcription processes causing eventual cell cycle arrest and potentially activation of pro-apoptotic signals (Figure 1.3) [54].

8 Advances in Metallodrugs

Regardless of the therapeutic success of cisplatin in the treatment of several types of tumors, its effectiveness is severely hindered by adverse side effects, viz., alopecia, ototoxicity, neurotoxicity, myelosuppression, and nephrotoxicity [55]. Another major drawback is tumor resistance, either acquired or intrinsic resistance [56]. However, considerable efforts are being made by many research groups around the world to mitigate the severe side effects, provide oral bioavailability, and overcome resistance issues of cisplatin; and consequently, a plethora of second generation plat-inum analogs were envisaged, viz., carboplatin, oxaliplatin, nedaplatin, heptaplatin, and satraplatin (Figure 1.4) [57].

Carboplatin and oxaliplatin have entered worldwide in chemotherapeutic drug regimens as a first-line treatment for colorectal cancer [58]. Carboplatin is primarily used against ovarian cancers; however, it has also found use in treating a diverse type of cancers including retinoblastomas, neuro- and nephroblastomas, brain tumors, as well as cancers of the head, neck, cer-vix, testes, breast, lung, and bladder [59]. Carboplatin has the same impli-cations as that of cisplatin, but with a different toxicity profile [60]. Another

INACTIVATION

INACTIVATION

INACTIVATION

INACTIVATION

Plasma Proteins, Albumin

OCTI-3INACTIVATION

MT

PassiveDiffusion

Bloodstream[CI–] = 100 mM

Cytoxol

[CI– ] = 4–10 mM

Aquation

NH3

NH3

NH3

NH3

OH2

NH3

+

H3N

H3N

H3N

CI

CICI

CI

CIPt

Pt

Pt

Pt

GSH

CTRI

Transcription Inhibition

O O

O

OOH

NH

HN OHHO

NH2 Active Efflux

through ATP7B

CELL DEATH!

DN

ARe

pair

Figure 1.3 The anticancer action of cisplatin revealing the extracellular and intracellular events that influence its anticancer activity. Reproduced with permission from ref [54(c)]. Copyright 2013 The American Chemical Society.

Metallodrugs in Medicine 9

front-line platinum anticancer drug oxaliplatin has gained global approval for combination chemotherapy treatment against colon cancers [61] and was subsequently approved for clinical use in countries like France and the United States [62]. Oxaliplatin features two chelating ligand groups with oxalate and R,R‒diaminocyclohexane (DACH) as leaving and non-leaving groups, respectively. Nedaplatin has been mainly used to treat head, neck, and esoph-agus cancers besides small cell lung and non‒small cell lung cancers in Japan [63]. The drug possesses cis ammine as non-leaving group along with a che-lating leaving group ligand as glycolate, which confers greater water solubility than cisplatin. Heptaplatin was developed in Korea and is being used against gastric cancer under the market name SunPla. The drug contains two types of chelating ligands, a malonate as a leaving group and 2‒(1‒methylethyl)‒1,3‒dioxolane‒4,5‒dimethanamine as its non-leaving ligand.

However, the search for efficacious drugs that overcome the limitations of platinum compounds such as severe side effects, high systemic toxicity, and incidence of drug resistance have motivated researchers to introduce non-platinum drugs into the drug regimens. No-platinum drug entities are likely to have different mechanism of action, bio-distribution, toxicity profile, and could be effective against human cancers that are poor chemo-sensitive or have become resistant to conventional platinum drugs.

Three-dimensional transition metals particularly Ti, Fe, Co, Cu, and Zn have invoked considerable interest as antitumor chemotherapeutics as these metal ions are site selective at physiological pH and are compatible to the biological system in contrast to platinum-based anticancer agents. Although essential metal ion that escapes from its normal metabolic

Carboplatin Oxaliplatin Nedaplatin

HeptaplatinSatraplatinLobaplatin

NH2

NH2

NH2

H2N

NH3

H3NH3N

H3NH3N

NH2

NH2

NH2O

O

O

O

O

O

Pt

PtPt Pt

Pt Pt

OCI

CI

O

O

O

O

O

O

O

O

OO

OOO

OO

O

O

Figure 1.4 Structure of anticancer platinum metallodrugs; carboplatin and oxaliplatin (approved), Carboplatin, Lobaplatin, heptaplatin, and satraplatin (in clinical trials).

10 Advances in Metallodrugs

pathway could show toxic effects in an organism, complexes of such metals can serve as effective cytotoxic agents. Among first row transition metal ions titanium complexes, viz., titanocenedichloride, (Cp2TiCl2) and budot-itane (Figure 1.5) have demonstrated pronounced antitumor properties and low toxic side effects [64]. Cp2TiCl2 which has entered in phase II clin-ical trial inhibits DNA synthesis rather than RNA and protein synthesis and titanium accumulates in nucleic acid rich regions in tumor cells after in vivo or in vitro administration [65]. The complex also showed weaker affinity to DNA bases and binds more strongly to phosphate backbone. Budotitane, which was the first non-platinum transition metal anticancer agent to be tested in clinical trials, was quite effective against a number of ascites tumors and induced colorectal tumors [66]. Clinical trials indicated that it was fairly well tolerated by patients with the dose limiting side effects being cardiac arrhythmia [67, 68].

Iron is the most significant essential metal ion in biology which serves as important cofactors of many redox enzymes [69]. Iron is vital for wide variety of metabolic processes including oxygen transport, DNA synthesis, and electron transport reactions. Many synthetic iron complexes have been reported displaying anticancer activities that are often linked to the redox reactions of Fe(II) or Fe(III) under physiological conditions [70]. One of notable example of anticancer compounds involving iron complexation is bleomycin which was clinically used to treat testicular carcinoma with high cure rates [71]. Bleomycin is a glycopeptide comprising a N-terminal metal-binding domain that coordinates to Fe(II) ion through five nitrogen donor atoms of amines, pyrimidine, and imidazole [72]. The coordination of dioxygen to Fe(II) is followed by one-electron oxidation which generates a bleomycin-Fe(III) OOH species. This species induced DNA damage as well as production of ROS, leading to apoptotic cell death [73]. Recently,

Ti

Cl

Cl

O

O

O O

Ti

OC2H5

C2H5O

Figure 1.5 Structure of Titanium anticancer agents: (a) Titanocene dichloride and (b) Budotitane.

Metallodrugs in Medicine 11

an organometallic compound Ferrocifen, an analog of Tamoxifen (which has been widely used in the clinic for the treatment of hormone depen-dent breast cancers) was discovered indicating a distinguished mode of antiproliferative activity (Figure 1.6) [74]. Another noteworthy example of iron complexes is a polypyridine iron(II) complex, Fe(II)–N4Py {N4Py = N,N–bis(2–pyridylmethyl)–N–bis(2–pyridyl)methylamine} which is syn-thetic bleomycin mimetic [75]. The complex was reported to cleave DNA efficiently under aerobic conditions and induced cell death and caused nuclear DNA damage [76].

Copper is one of widely distributed in the biological system and is the most familiar redox metal accessible within the cellular potential range [77]. Due to the plasticity and participation of copper as an integral part of the active site of metalloproteins (superoxide dismutase, ceruloplasmin, cytochrome oxidase, and tyrosinase), it familiarizes its coordination with the human body’s functions [78]. Copper binds to electron rich nucleic acids (DNA/RNA) with higher affinity than any other divalent cation and induces conformational changes in polynucleotides and bio-membranes. The altered metabolism of cancer cells and the differential response between normal and tumor cells to copper is the basis for the development of copper complexes endowed with antitumor properties [79].

Ruiz-Azuara et al. have synthesized a series of Cu(II) complexes with diimine ligand donors having the trade name “CasiopeinasⓇ, (Cas)” as antitumor chemotherapeutics (Figure 1.7) [80, 81]. These compounds are mixed chelate copper(II) complexes with a general condensed for-mula [Cu(N–N)(A–A)][NO3], where N–N represents neutral diimine donors, either phen or bipy, A–A stands for uninegative N–O or O–O donors, either aminoacidates or acetylacetonate. The activity of Cas II–gly, [Cu(1,4–dimethyl–1,10–phenanthroline)(glycine)NO3], a novel anti-cancer agent, was tested against two cell lines, L1210 (murine leukemia)

NN

N

N

FeR

R

N

H3CCN

H3CCN

2+

NOH

NN

HO

FeN N

NCCH3

2+

R = H, Ph

Fe

OH

OH

(a) (b)

Figure 1.6 Examples of some iron anticancer agents: (a) Ferrocifen (ferrocene derivative of tamoxifene) and (b) Iron(II) pentapyridyl complexes.

12 Advances in Metallodrugs

and CH1 (human ovarian carcinoma). It was observed Cas II–gly was highly active against these cell lines, including cell lines resistant to cis-platin and mechanism of cell death was both via apoptosis and necrosis [82]. Another variant of the “Casiopeina” series, [Cu–(acetylacetonato)(4,4′–dimethyl–2,2′–bipyridine](NO3), (CasIII–ia), was found to exhibit antineoplastic effects on glioma C6 [83].

Ruthenium(II) complexes are rapidly becoming a prime focus for the development of new more efficacious metal-based anticancer drug entities due to their unique spectroscopic and electrochemical properties [84, 85]. Ruthenium is well suited for pharmacological applications as it offers vari-ous oxidation states (II, III, and IV) under physiologically conditions [86]. Plethora of ruthenium complexes have been synthesized and have success-fully demonstrated significant cytotoxic and antimetastatic properties with reduced side effects [87]. The first successful breakthrough in the area of ruthenium-based chemotherapeutics was achieved by B. K. Keppler et al. who synthesized imidazolium [trans–RuCl4(1H–imidazole)(DMSO–S)] (NAMI–A) and indazolium [trans–RuCl4(1H–indazole)2] (KP1019), as a substitute to platinum-based drugs (Figure 1.8). These drugs have suc-cessfully completed phase I clinical trials and are now undergoing further clinical evaluation [88, 89].

Both NAMI–A and KP1019 are ionic Ru(III) compounds bearing struc-tural novelty possessing negatively charged octahedral metal center coor-dinated to heterocyclic nitrogen donor ligands and equatorial chlorides; a protonated form of the heterocyclic nitrogen ligands as counter ions that are replacable by sodium or other cations [90]. NAMI–A in solution phase involves both loss of Cl− and DMSO. NAMI–A is the most intensively stud-ied ruthenium anticancer complexes because of its ability to prevent the metastasis formation or inhibit the growth of secondary tumor cells while KP1019 is active only against primary cancers [91]. KP1019 has entered in the clinical trials after it demonstrated in vitro cytotoxic activity against

Cu

H2NC

O

O

N N

CH3H3C+

NO3_

Cu

+

NO3_

N N

CH3H3C

O O

Figure 1.7 Structure of Cas II–gly and III–ia.

Metallodrugs in Medicine 13

cisplatin-resistant human colon carcinoma cell lines [92] along with effi-cient in vivo activity against various tumor types. Pertinent to mention, Ru(II) compounds that are administered to the patient are not as the active species rather Ru(III) complexes are first reduced into a more active Ru(II) form (Scheme 1.1). The plausible mechanistic hypothesis for Ru(III) com-pounds was attributed on “activation by reduction” mechanism, accord-ing to which the Ru(III) complexes act as prodrugs that can be reduced to Ru(II) active species in the hypoxic (therefore reducing) environ-ment of cancer cells [93]. The hydrolysis reaction of Ru–X bonds to give ruthenium‒aqua species (aquation) is an important aspect of the thera-peutic behavior for ruthenium complexes. The corresponding aqua species

HN

HN

HN

N

N

N NH

NH

SO CH3

(a) (b)

CH3

CI

CI CI NH

HN +

+

CICI

CI CI

CI

Ru

Ru

Figure 1.8 Ru(III) anticancer compounds currently in clinical trials: (a) imidazolium [trans-RuCl4(1H–imidazole)(DMSO–S)] (NAMI–A) and (b) indazolium [trans-RuCl4 (1H-indazole)2] (KP1019).

Ru3+

Ru2+

Ru2+

Ru3+

+H2OTarget site

OH2

–X

OH

Active Species

–H++H+A prodrug

Scheme 1.1 A generalized scheme depicting possible action for Ru(III) prodrugs invoking “activation by reduction” hypothesis (X = Cl−,Br−, I−).

14 Advances in Metallodrugs

exist over a wide range of pH, but for pH > pKa, the hydroxo species formed by deprotonation are predominant. Since, the hydroxide is a less labile ligand than water, it will not so easily be displaced by biomolecule targets. “Aquation” of the chloro complexes may be suppressed extracellularly due to high chloride concentrations (0.1 M) but because of lower intracellular Cl‒ concentrations (4–25 mM), the aquation reaction is highly possible.

Many ruthenium compounds have been found are non-toxic and have been quite selective for cancer cells. This has been attributed to the ability of ruthenium to mimic iron in binding to biomolecules. As cancer cells overexpress transferrin receptors to satisfy their increased demand for iron, ruthenium-based drugs have been found to be delivered more effi-ciently to cancer cells [94].

In recent years, half-sandwich–configured organoruthenium(II)–arene scaffold have emerged as a versatile tool for the design novel anticancer agents because their biological activity and pharmacological properties can easily be modulated by ligand selection [95]. The different mode of action is a consequence of their high lipophilicity that favor better cellular uptake; and the presence of labile ligands, viz., chlorido/carboxylato, favor the extracellular binding with the drug target. Besides possessing suppos-edly low general toxicity and high selectivity of ruthenium-arene com-plexes towards cancer cells, the big reasons for the flourishing design of arene-ruthenium–based anticancer drugs are the amphiphilic properties of the arene ruthenium unit, which provides the hydrophobic nature to the arene ligand counter balanced by the hydrophilic metal center [96]. The pioneering work of Paul J. Dyson and P. J. Sadler in the field of anticancer organometallics led to successful revelation of two lead Ru(II)‒arene anti-cancer agents, RAPTA–C, and RAED which are at an advanced preclinical development stage (Figure 1.9) [97, 98].

Ru ClH2N

NH2

+

RuCl

Cl

P

N

N

N

(a) (b)

PF6

_

Figure 1.9 Structures of anticancer organoruthenium complexes (a) RAPTA–C ([RuII(cym)(PTA)Cl2], PTA = 1,3,5–triaza–7–phosphatricyclo[3.3.1.1]decane; cym = η6–p–cymene) and (b) RAED ([RuII(η6–biphenyl)(en)Cl]+.